AKT-induced tamoxifen resistance is overturned by RRM2 inhibition.
Mol Cancer Res, 2014/3;12(3):394-407.
Shah KN[1], Mehta KR, Peterson D, Evangelista M, Livesey JC, Faridi JS
Affiliations
PMID: 24362250DOI: 10.1158/1541-7786.MCR-13-0219
Impact factor: 6.333
Abstract
unlabelled: Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)-mediated approaches significantly reversed the tamoxifen-resistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis.
implications: These findings identify RRM2 as an AKT-regulated gene, which plays a role in tamoxifen resistance and may prove to be a novel target for effective diagnostic and preventative strategies.
MeSH terms
Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms; Cell Growth Processes; Cell Movement; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Humans; Isoenzymes; MCF-7 Cells; Mice; Neoplasms, Hormone-Dependent; Proto-Oncogene Proteins c-akt; Ribonucleoside Diphosphate Reductase; Signal Transduction; Tamoxifen; Xenograft Model Antitumor Assays
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